Cardiovascular Mortality In Rheumatoid Arthritis Research Articles

Rheumatoid Arthritis and Mortality in End Stage Renal Disease.

To determine whether rheumatoid arthritis (RA) is a risk factor for cardiovascular disease (CVD) events, all-cause mortality and cardiovascular mortality in End Stage Renal Disease (ESRD). Cohort study of adult patients with ESRD in the United States Renal Data System (USRDS) with RA and a 5% random sample of those without RA. CVD events, all-cause mortality and cardiovascular mortality were determined in those with RA compared to those without RA using Cox Proportional Hazards modeling. 2,824 subjects, 407 with RA and 2,417 without RA, were included in the analyses. The duration of the study was up to 5 years, depending on mortality and initiation of dialysis. There were no significant differences in CVD events by RA status (n = 311 [76.4% RA] vs. n = 1936 [80.1% without RA], p = 0.09). Subjects with RA had a significantly shorter mean time in months from start of dialysis to an incident CVD event (20.1 ± 12.2 vs. 21.2 ± 14.1, p < 0.01) than those without RA. In multivariable adjusted models, RA was not associated with an increased risk for all-cause mortality (aHR = 1.09, 95%CI 0.94-1.27) or cardiovascular mortality (aHR = 0.95, 95% CI 0.74-1.22) within 5 years. Risk factors for all-cause mortality and cardiovascular mortality in RA included older age and a higher Charlson comorbidity index (CCI). Clinicians should be aware that persons with RA who develop ESRD incur cardiac events sooner than the general population. However, RA is not an independent risk factor for all-cause or cardiovascular mortality in ESRD.

Expansions of Cytotoxic CD4+CD28- T Cells Drive Excess Cardiovascular Mortality in Rheumatoid Arthritis and Other Chronic Inflammatory Conditions and Are Triggered by CMV Infection.

A large proportion of cardiovascular (CV) pathology results from immune-mediated damage, including systemic inflammation and cellular proliferation, which cause a narrowing of the blood vessels. Expansions of cytotoxic CD4+ T cells characterized by loss of CD28 (“CD4+CD28− T cells” or “CD4+CD28null cells”) are closely associated with cardiovascular disease (CVD), in particular coronary artery damage. Direct involvement of these cells in damaging the vasculature has been demonstrated repeatedly. Moreover, CD4+CD28− T cells are significantly increased in rheumatoid arthritis (RA) and other autoimmune conditions. It is striking that expansions of this subset beyond 1–2% occur exclusively in CMV-infected people. CMV infection itself is known to increase the severity of autoimmune diseases, in particular RA and has also been linked to increased vascular pathology. A review of the recent literature on immunological changes in CVD, RA, and CMV infection provides strong evidence that expansions of cytotoxic CD4+CD28− T cells in RA and other chronic inflammatory conditions are limited to CMV-infected patients and driven by CMV infection. They are likely to be responsible for the excess CV mortality observed in these situations. The CD4+CD28− phenotype convincingly links CMV infection to CV mortality based on a direct cellular-pathological mechanism rather than epidemiological association.

Cytomegalovirus as a Driver of Excess Cardiovascular Mortality in Rheumatoid Arthritis: A Red Herring or a Smoking Gun?

#### Cytomegalovirus as a Driver of Excess Cardiovascular Disease in Rheumatoid Arthritis: The Facts in Short Rheumatoid arthritis (RA) is the most common inflammatory arthritis worldwide. Apart from its well-known manifestations involving the joints (eg, deformity, swelling, and synovial inflammation), there are widespread, extra-articular manifestations that also involve the cardiovascular system.1 The consequences of cardiovascular involvement are often serious; cerebrovascular disease, ischemic heart disease, and cardiovascular disease (CVD)–associated death are ≤50% higher in the context of RA leading to a reduction of life-expectancy in these patients of 3 to 10 years compared with the general population.1 To date, no satisfactory explanation of this phenomenon has been found, or maybe, it has been overlooked? This Viewpoint argues that cytomegalovirus (CMV) is a major contributor to the excess of CVD observed in RA. For over 2 decades, CMV has been implicated …

Vitamin D receptor GATG haplotype association with atherosclerotic disease in patients with rheumatoid arthritis

IntroductionAn association between the vitamin D receptor (VDR) GAT haplotype and coronary artery disease (CAD) in type-2 diabetes has recently been described. Since cardiovascular mortality in rheumatoid arthritis (RA) is comparable to that observed for patients with type-2 diabetes, we aimed to determine if VDR GAT haplotype is also associated with atherosclerotic disease in RA. Material and Methods591 Northern Spanish RA patients were genotyped for 4 VDR polymorphisms (rs731236 A/G; rs7975232 A/C; rs1544410C/T; rs2228570 G/A). Atherosclerotic disease was established by the presence of carotid plaques in carotid ultrasound. ResultsVDR rs7975232 AA genotype was increased in RA patients with plaques (p = 0.045, OR = 1.46 [1.01–2.18]). More importantly, the frequency of carotid plaques was significantly increased in RA patients who carried the GATG haplotype (p = 0.009, OR = 1.56 [1.09–2.42]). ConclusionOur results suggest a potential VDR GATG haplotype association with atherosclerotic disease in RA patients.

The impact of traditional cardiovascular risk factors on cardiovascular outcomes in patients with rheumatoid arthritis: a systematic review and meta-analysis.

BackgroundRheumatoid arthritis (RA) is known to increase the risk of cardiovascular (CV) disease. However, the individual impact of traditional CV risk factors in RA is unknown.ObjectiveTo assess the strength of the association between individual CV risk factors and rate of either myocardial infarction (MI), combined CV morbidity (MI, angina pectoris, heart failure, stroke, and peripheral arterial disease (PAD)) or CV mortality in RA patients.MethodsRA studies reporting traditional CV risk factors [hypertension, type 2 diabetes (T2D), smoking, hypercholesterolaemia, obesity, and physical inactivity] as exposures and MI, CV morbidity (MI, angina, heart failure, stroke, and PAD combined) or CV mortality alone as outcomes were searched until March 2013 using MEDLINE, Scopus and Cochrane. Meta-analyses combined relative risk (RR) estimates from each study where either the RR and 95% confidence intervals or where raw counts were available.ResultsTen studies reporting sufficient data for inclusion into meta-analyses were identified. Relevant data was available for each risk factor and MI and CV morbidity but no studies reported on CV mortality. Risk of MI increased in RA patients with hypertension (RR 1.84, 95% CI 1.38, 2.46) and T2D (RR 1.89, 95% CI 1.36, 2.63). CV morbidity increased with hypertension (RR 2.24, 95% CI 1.42, 3.06), T2D (RR 1.94, 95% CI 1.58, 2.30), smoking (RR 1.50, 95% CI 1.15, 1.84), hypercholesterolaemia (RR 1.73, 95% CI 1.03, 2.44) and obesity (RR 1.16, 95% CI 1.03, 1.29) but not with physical inactivity (RR 1.00, 95% CI 0.71, 1.29).ConclusionHypertension, T2D, smoking, hypercholesterolaemia and obesity increased CV risk in patients with RA. These results highlight the importance of managing CV risk factors in RA, similarly to non-RA patients.

Glucocorticoid Dose Thresholds Associated With All‐Cause and Cardiovascular Mortality in Rheumatoid Arthritis

To delineate daily and cumulative glucocorticoid dose thresholds associated with increased mortality rates in rheumatoid arthritis (RA). We studied RA patients recruited from rheumatology clinics. Annually, we assessed the glucocorticoid dose, demographic, socioeconomic, clinical, and laboratory features of RA, cardiovascular (CV) risk factors, and vital status. We used Cox proportional hazards regression to assess associations between the daily or cumulative glucocorticoid dose and death, adjusting for potential confounders and for the propensity to receive glucocorticoids. We tested strata of the glucocorticoid dose to delineate the threshold associated with death. We studied 779 RA patients with a total of 7,203 person-years of observation, during which 237 of them died, yielding a mortality rate of 3.2 per 100 person-years (95% confidence interval [95% CI] 2.8-3.7). One hundred twenty of the deaths were due to CV causes, yielding a CV mortality rate of 1.8 (95% CI 1.5-2.1). Exposure to glucocorticoids was associated with a dose-dependent increase in death from all causes, with a ratio (HR) of 1.07 per mg of prednisone per day (95% CI 1.05-1.08). Compared to patients who were not receiving corticosteroids, the minimum daily prednisone dose threshold associated with an increase in all-cause mortality was 8-15 mg, with an adjusted HR of 1.78 (95% CI 1.22-2.60). For the cumulative dose of glucocorticoids, the minimum dosage associated with all-cause mortality was 40 gm (HR 1.74 [95% CI 1.25-2.44]). Glucocorticoid use in RA is associated with a dose-dependent increase in mortality rates, with a daily threshold dose of 8 mg, at which the number of deaths increased in a dose-dependent manner. These findings may assist clinicians in selecting the appropriate glucocorticoid dosage for RA patients who require these agents.

Inflammatory arthritis as a novel risk factor for cardiovascular disease

Cardiovascular disease (CVD) comorbidity is a significant issue for the inflammatory arthritides (IA). There is a wealth of mortality studies showing increased cardiovascular mortality in rheumatoid arthritis (RA) and the evidence suggests that the same is likely to be true of psoriatic arthritis (PsA) and ankylosing spondylitis (AS). CVD co-morbidity is due to ischaemic pathologies driven by accelerated atherosclerosis and relates to the increased prevalence and clustering of classical risk factors, which may also be affected by treatments for IA, and their interplay with novel risk factors, namely systemic inflammation.Currently we are unable to quantify the contribution that classical and novel risk factors make to an individuals' CVD risk and specific algorithms need to be developed and validated in RA, PsA and AS to facilitate clinical management. Furthermore, large clinical trials are required to assess the effect of lifestyle modifications, primary prevention strategies and effective immunosuppression on hard CVD endpoints. However, in the meantime, a pragmatic approach should be adopted towards CVD risk management. Consensus opinion has generated guidelines for the management of CVD risk in IA and we discuss the importance of assessing each individual for CVD risk and establishing a system for routine risk factor identification alongside a commitment to treat identified risk factors to specific targets.

Fish oil and rheumatoid arthritis: past, present and future

Meta- and mega-analysis of randomised controlled trials indicate reduction in tender joint counts and decreased use of non-steroidal anti-inflammatory drugs with fish-oil supplementation in long-standing rheumatoid arthritis (RA). Since non-steroidal anti-inflammatory drugs confer cardiovascular risk and there is increased cardiovascular mortality in RA, an additional benefit of fish oil in RA may be reduced cardiovascular risk via direct mechanisms and decreased non-steroidal anti-inflammatory drug use. Potential mechanisms for anti-inflammatory effects of fish oil include inhibition of inflammatory mediators (eicosanoids and cytokines), and provision of substrates for synthesis of lipid suppressors of inflammation (resolvins). Future studies need progress in clinical trial design and need to shift from long-standing disease to examination of recent-onset RA. We are addressing these issues in a current randomised controlled trial of fish oil in recent-onset RA, where the aim is to intervene before joint damage has occurred. Unlike previous studies, the trial occurs on a background of drug regimens determined by an algorithm that is responsive to disease activity and drug intolerance. This allows drug use to be an outcome measure whereas in previous trial designs, clinical need to alter drug use was a 'problem'. Despite evidence for efficacy and plausible biological mechanisms, the limited clinical use of fish oil indicates there are barriers to its use. These probably include the pharmaceutical dominance of RA therapies and the perception that fish oil has relatively modest effects. However, when collateral benefits of fish oil are included within efficacy, the argument for its adjunctive use in RA is strong.

Increased platelet activation markers in rheumatoid arthritis: Are they related with subclinical atherosclerosis?

Atherosclerotic cardiovascular mortality is increased in rheumatoid arthritis (RA) patients. We evaluated the association of inflammatory response with platelet, endothelial, coagulation activation parameters; and subclinical atherosclerosis in RA patients. We included 27 RA patients (21 female; six male) and 19 healthy subjects (14 female; five male). Disease activity score (DAS28) in RA patients was calculated; and patients were divided into two groups as active and inactive. Flow cytometry was used to determine platelet CD62P expression, platelet microparticles (PMP), platelet-monocyte (PMC) and platelet-neutrophil complexes (PNC). Plasma E-selectin, thrombin-antithrombin (TAT) complex, and serum sCD40L levels were determined by ELISA. The intima-media thickness (IMT) of carotid arteries was determined by B-mode ultrasonography. In RA patients, platelet CD62P expression (p < 0.001), PMC (p = 0.037) and sCD40L (p < 0.001) levels were increased when compared to the control group. PNC (p = 0.07) and TAT levels (p = 0.1) were non-significantly higher, and PMP level (p = 0.075) was nonsignificantly lower in RA patients. Soluble E-selectin level was significantly higher in the active RA group than in the inactive RA group (p = 0.009). There was no correlation between carotid IMT and activity markers, the evaluated parameters (p > 0.05).The increase in markers of active platelets, CD62P and sCD40L, and PMC levels might be associated with the increased cardiovascular mortality in RA. Nevertheless, none of these parameters were associated with carotid IMT: this suggests that one cross-sectional value might not be a good marker for atherosclerosis.

HLA–DRB1 and persistent chronic inflammation contribute to cardiovascular events and cardiovascular mortality in patients with rheumatoid arthritis

Cardiovascular (CV) disease is the most common cause of mortality in patients with rheumatoid arthritis (RA). We assessed the contribution of epidemiologic features, clinical features, routine laboratory markers of inflammation, and HLA-DRB1 alleles to CV mortality in patients with RA prospectively followed at a single referral center in Spain. Patients fulfilling the 1987 American College of Rheumatology classification criteria for RA seen at the rheumatology outpatient clinic of Hospital Xeral-Calde, Lugo between March and September 1996 were included. HLA-DRB1 phenotype, epidemiologic data, and clinical data were assessed at that time. Patients were prospectively followed and clinical records were examined until patient's death or September 1, 2005. A total of 182 consecutive patients were assessed. Compared with the general Spanish population, the age- and sex-standardized mortality ratio by CV cause was 1.78. CV mortality adjusted by age at disease onset and sex was associated with chronic inflammation determined by C-reactive protein level (CRP; hazard ratio [HR] 1.14, P < 0.001) and erythrocyte sedimentation rate (ESR; HR 1.05, P = 0.003). Patients with HLA-DRB1*04 shared epitope alleles (HR 4.15, P = 0.030), in particular those HLA-DRB1*0404 positive (HR 6.65, P = 0.002), had increased risk of CV mortality. Increased risk of CV events was also associated with CRP level (HR 1.09, P = 0.001), ESR (HR 1.03, P = 0.003), and HLA-DRB1*0404 (HR 4.47, P = 0.002). Our results suggest that a chronically high inflammatory response in genetically predisposed individuals promotes an increased risk of CV events and CV mortality in RA.

Paradoxical Effect of Body Mass Index on Survival in Rheumatoid Arthritis

Despite high cardiovascular mortality in rheumatoid arthritis (RA), few studies of body mass index (BMI) and obesity as risk factors for death in RA have been published. We estimated the effect of BMI on survival in a cohort of 779 patients with RA adjusting for comorbidity, RA disease severity, erythrocyte sedimentation rate (ESR), and other potential confounders. The cohort accrued 123 deaths in 3460 person-years (3.6 deaths per 100 person-years; 95% confidence interval [CI], 3.0-4.2). The BMI was inversely associated with mortality. Patients with BMIs of 30 or higher had the lowest mortality, 1.7 deaths per 100 person-years (95% CI, 1.1-2.5). Mortality was higher in each lower BMI category, reaching its highest rate among patients with BMIs lower than 20 with 15.0 deaths per 100 person-years (95% CI, 9.9-23.0). The survival advantage of high BMI was independent of RA onset age, RA duration, sex, ethnic group, socioeconomic status, smoking status, and use of methotrexate but was lost on adjusting for comorbidity and RA severity. We observed an interaction between BMI and ESR, where the BMI protective influence occurred only if the ESR was low. The BMI x ESR interaction was independent of all covariates, including comorbidity and RA severity. Body mass has a paradoxical effect on mortality in RA. Patients with high BMI have lower mortality than thinner patients. This effect is mediated in part by comorbidity. The effect of body mass on survival seems to be modified by the level of systemic inflammation.

It's all in the blood: circulating endothelial progenitor cells link synovial vascularity with cardiovascular mortality in rheumatoid arthritis?

It's all in the blood: circulating endothelial progenitor cells link synovial vascularity with cardiovascular mortality in rheumatoid arthritis?

Prognostic importance of low body mass index in relation to cardiovascular mortality in rheumatoid arthritis

Various etiologic mechanisms have been implicated in the observed increase in cardiovascular mortality in rheumatoid arthritis (RA). Body mass index (BMI) is associated with cardiovascular mortality in the general population. This study compared the effect of BMI on cardiovascular mortality in a population-based cohort of subjects with RA with that in a cohort of individuals without RA from the same population. The RA cohort comprised all members of an incidence cohort of Rochester, Minnesota residents ages > or =18 years who were first diagnosed with RA (by the American College of Rheumatology 1987 criteria) from 1955 through 1994. An age- and sex-matched comparison cohort of subjects without RA was assembled. Both cohorts were followed up longitudinally through their complete (inpatient, outpatient) medical records beginning at age 18 years and continuing until death, migration, or January 1, 2001, and the details of weight and height changes during this period were recorded. High BMI was defined as a BMI >30 kg/m(2) and low BMI as <20 kg/m(2). Cox regression models were used to estimate the effect of BMI on cardiovascular mortality after accounting for traditional cardiac risk factors and malignancies. RA subjects with low BMI at incidence had a significantly higher risk of cardiovascular death (hazard ratio [HR] 3.34, 95% confidence interval [95% CI] 2.23-4.99) compared with non-RA subjects with normal BMI, after adjusting for age, sex, personal cardiac history, smoking status, and presence of diabetes, hypertension, and malignancies. RA subjects with normal BMI at incidence who experienced low BMI during followup also had a higher risk of cardiovascular death (HR 2.09, 95% CI 1.50-2.92) when compared with non-RA subjects who maintained normal BMI throughout followup. Among patients with RA, low BMI is associated with a significantly increased risk of cardiovascular death.

Screening for atherosclerosis in patients with rheumatoid arthritis: Comparison of two in vivo tests of vascular function

Inflammation appears to play a central role in atherosclerosis, and endothelial damage mediated by systemic inflammation may contribute to the increased cardiovascular mortality in rheumatoid arthritis (RA). Brachial artery flow-mediated dilatation (FMD) and pulse wave analysis (PWA) are measures of vascular function. The aim of this study was to determine if FMD and PWA are abnormal in patients with RA. Twenty-five RA patients and 25 matched healthy controls were studied. All were free of traditional cardiovascular risk factors. FMD was measured in all subjects. PWA was performed in 18 RA patients and 18 controls, with results expressed as large and small artery compliance (C1 and C2). Modified Sharp scores were calculated in 13 RA patients. Results (mean +/- SD) in RA patients and controls, respectively, were as follows: FMD 107.6 +/- 4.6% versus 108.5 +/- 4.1% (P = 0.49), C1 14.8 +/- 2.8 ml/mm Hg x 10 versus 17.9 +/- 3.1 ml/mm Hg x 10 (P = 0.0033), C2 4.5 +/- 2.3 ml/mm Hg x 100 versus 7.7 +/- 3.7 ml/mm Hg x 100 (P = 0.0039). There was an inverse correlation between C2 and modified Sharp scores in the RA patients (Spearman's rho -0.69, P = 0.0085). FMD was normal in these RA patients, whereas arterial compliance was markedly reduced. PWA appears to be a more sensitive measure of vascular dysfunction than FMD in RA and may be the preferred surrogate marker of vascular dysfunction in longitudinal studies of RA patients. The inverse correlation between C2 and the modified Sharp score, a measure that reflects disease activity over time, supports the notion that chronic inflammation plays a role in RA-associated atherosclerosis.